Differential Diagnosis for LGS and Challenges in Managing Seizures


Tracy Dixon-Salazar, PhD, and Kelly Knupp, MD, emphasize key identifiers for the diagnosis of Lennox-Gastaut Syndrome and challenges in managing seizures in these patients.

Joseph E. Sullivan, MD: I do want to mention one thing that we all brought up in terms of classic EEG features of Lennox-Gastaut. I certainly have sent a few patients who have nothing else to suggest on Lennox-Gastaut but they get an EEG, some slow spike and wave slow spike and wave during sleep. And they are sent to me second opinion for Lennox-Gastaut, I alluded to you, you need the clinic EEG and EEG pattern is the pattern that is most often associated with that clinical picture of Lennox-Gastaut but if someone else did everything it would be unusual but if a patient fit a seizure type and maybe didn’t have a slow spike, I still would approach them in that same way as Lennox-Gastaut. The same thing, if someone did not have any of those seizure types only had generalized tonic clonic seizures and then had slow spike and wave on their EEG, I would not give that patient Lennox-Gastaut. Do you both agree with the fact? Feel free to disagree.

Kelly Knupp, MD: If you had a patient with just generalized tonic clonic seizures but they had slow spike and wave and PFA on their EEG, I would be looking really closely to see if they have tonic seizures associated with PFA.

Joseph E. Sullivan, MD: Agree.

Kelly Knupp, MD: It may just be so subtle that you miss it, but it’s also important to keep in mind that just as this evolves probably at typical ages and of course every child hasn’t read the book and so not everybody does it exactly when they should. It also is something that does sometimes go away as children get older, and if somebody has missed the window in those 3 to 10-year-old age, it’s quite possible that we could have a teenager or young adult who otherwise fits Lennox-Gastaut, but no longer has those spike and wave PFA. This is something that people pay attention to more in clinical trials because many clinical trials trying to ensure that they have inappropriate diagnosis of Lennox-Gastaut will require slow spike and wave in PFA, but if you are going to require that for adults with Lennox-Gastaut, it’s going to be hard to find it. You must go back to the earlier records to look for it.

Tracy Dixon-Salazar, PhD: The reality is as you know as scientists, we need these rigorous definitions as testing theories. If we want to learn to treat the Lennox-Gastaut network we need patients that have the classical EEG features. When you look in the communities that we serve, all the developmental and epileptic encephalopathies that have seizures as a main driver are dealing with – that we are living the same journey, we see the same doctors, we are on the same treatments, we all tend to be super refractory. Seizures are just the tip of the iceberg in all of us, but what distinguishes us is that there is developmental piece of it. We are much more drawn to a treatment that has been tested in our super refractory LGS population or Dravet population than someone with say adult-onset temporal lobe epilepsy, that there is not that developmental component that has further complicated the epilepsy. But the reality is we are all on the same journey, when you are in the community we unite. We divide on the science, but we unite on everything else as it relates to the developmental and epileptic encephalopathy including Dravet, tuberous sclerosis, I don’t even know how many there are now.

Dr. Joseph Sullivan: Exactly.

Kelly Knupp, MD: Many more than we can mention.

Tracy Dixon-Salazar, PhD: I guess one other thing I would just say is that whenever you see LGS you should be thinking what is their LGS secondary to?

Kelly Knupp, MD: That’s what I was about to say.

Tracy Dixon-Salazar, PhD: We know the critical malformations. We know that de novo genetic mutations. We know that hypoxic ischemia and other birth injuries, stroke at birth, post chemotherapy seizures that involve LGS, down syndrome kids who develop seizures and evolve into LGS. TSC is a great example. Many of these babies, something like 40% to 50% of the kids that develop IS from their TSC mutation will evolve into LGS. What is the etiology, now you’re dealing with whatever the etiology is and this LGS network that has formed and the way that it has impacted development. I don’t know the relation, but I have heard some people say you can Dravet and LGS and I heard other people say absolutely not they can never exist in the same patient. We have patients with both in our community and I am not going to fight with them, they are welcome to be supported by us.

Kelly Knupp, MD: But that emphasizes the point that it is important to look for that etiology because it may impact treatment. There are children with Dravet syndrome with SCN9A mutations who check all the boxes for LGS. It’s important to make that diagnosis because we commonly use sodium channel blockers in children with LGS but if somebody has SCN9A mutation, we would not use the sodium channel blocker in that patient. In some ways, we may have 2 paths that we need to look at for as we are looking at treatment once we have the LGS diagnosis as well as the etiology.

Tracy Dixon-Salazar, PhD: I would just add, would it hesitate to give the LGS diagnosis, the LGS Foundation held the meeting of minds last year, a seminar and Dennis Dlugos said we tend to hesitate to give you just diagnosis because parents don’t want to hear it, it’s bad, there is not a lot we can do and the science is changing first of all, so there is a lot we can do. And second, we have an amazing community of support. We don’t have cures and we are very unlikely that we are going to get seizure freedom. We are not going to give up looking for it, but if these two have a community that can help you manage to attempt to manage the disease, I would suggest we not hold back.

Joseph E. Sullivan, MD: Agreed and something that I am curious to hear your thoughts on. Finding the more precise diagnosis. In my opinion, just because you think you may have one doesn’t mean that’s the right one. There have been some papers that have come up, just because maybe you had a little stroke in the neonatal period, maybe you should still do some genetic testing to see if there is something else going on because that could have a lot of potential treatment implications down the road.

Kelly Knupp, MD: Particularly yes, we are having more gene modifying therapies in trials. You very well can have LGS secondary to gene that has a gene modulatory therapy that is in trials, and we want to make sure that you have access to that.

Tracy Dixon-Salazar, PhD: My own daughter has LGS secondary to calcium channel over-activation disorder. She has calcium channel mutations and the only drug that she has ever responded to has been something targeted towards her genetics and her genomics. We are a big proponent of that. Now about half of the LGS population is genetic and the other half is acquired and I don’t think we have looked at the acquired epilepsies that have evolved into LGS as closely genetically. You are right Dr Sullivan. I think there is element of we need to look there and see but we are big proponents of any sort of precision type of therapy or genomic medicine approach to our families because it really can make a difference.

Joseph E. Sullivan, MD: We have previously talked about Dravet, how it’s more homogeneous but yet it’s still a spectrum disorder. I guess LGS we would agree is much more heterogeneous with so many different background causes, but it still is a spectrum disorder and there still is going to be value to the community. I say this with any syndrome diagnosis I make like yes you can go online, and you can look it up but no one is your child, every child is going to act a little bit different. Yes, you may read some common themes and you may be able to reach out to other families to get support on some of those common themes but that really in my opinion isn’t something – even with the same genetic diagnosis with LGS phenotype those are still going to be different to different patients. I am just curious. In your foundation when you have families, how do they deal with that in terms of spectrum and finding someone that is more aligned with what they are living day to day.

Tracy Dixon-Salazar, PhD: One of the things that came out of Rare Epilepsy Networks Study that was funded by PCORI was that when you looked across a bunch of different DEEs and you asked the question, how many seizures has your loved one had in the last 6 months. I remember Dravet of the top of my head, the answer was 100s, tuber sclerosis 100s, LGS was 1000s. The unifying theme in the LGS community, not that we are going to win any prizes for this, the seizures all suck. They're horrible. But we’re talking – our families are shifted. You often will hear people say epilepsy is more than seizures, we’re not really singing that tune over in the LGS space because if you don’t get the seizures which are often happening daily and my daughter was having 5 to 10 on her best day, 100s, too many to count on her worst day and that was our life for 16 years and most of our family has never achieved any stability from that. If you don’t do something about the seizures how are any of the other things like gait or GI [gastrointestinal] issues or sleep or behavior going to get better. Often people ask what’s the difference and for us it’s just we’re constantly dealing with the seizures and the things that are associated with those. Somebody recently asked me, why don’t we talk as much about SUDEP in the LGS community as they do in Dravet, and I think it’s because we’re just constantly trying to keep our kid alive from seizures and out of the emergency room. Their status, my kid had three skull fractures, had injuries, their aspiration pneumonia which is the number one killer in patients with LGS and there are cluster seizures. There is all of these sorts of things wasting away because we can’t stop the seizures and now they are in a coma, so we just spend our time thinking about all the death options and we are only worried about SUDEP in sleep. It’s a confined time period for the SUDEP that we get to worry about it, but we are just more thinking about just a constant barrage of seizures and the medical intervention and constant medical oversight that’s needed, do they need oxygen, make sure they don’t aspirate, do you need to do this and that. Those are the biggest differences but you’re right, our families are unified around this common theme of seizures but they are coming from all these etiologies that each is so uniquely rare but they are often in multiple communities. They will be in the hypoxic ischemia community; they will be in Dravet community and they will be in our community.

Transcript Edited for Clarity

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